Targeted, precise care of patients with sepsis will require a better understanding of mechanisms underlying sepsis and accurate methods to prognosticate sepsis syndromes. Despite decades of work, many sepsis patients go unrecognized by healthcare professionals without receiving recommended treatment. Vincent et al., “The SOFA (Sepsis-related Organ Failure Assessment) score to describe organ dysfunction/failure. On behalf of the Working Group on Sepsis-Related Problems of the European Society of Intensive Care Medicine” Intensive Care Med 1996; 22(7):707-710; Le Gall et al., “The Logistic Organ Dysfunction system. A new way to assess organ dysfunction in the intensive care unit. ICU Scoring Group” JAMA: the journal of the American Medical Association 1996; 276(10):802-810; Marshall et al., “Multiple organ dysfunction score: a reliable descriptor of a complex clinical outcome” Critical Care Medicine 1995; 23(10):1638-1652; Shapiro et al., “A prospective, multicenter derivation of a biomarker panel to assess risk of organ dysfunction, shock, and death in emergency department patients with suspected sepsis” Crit Care Med 2009; 37(1):96-104; Opal S M., “Concept of PIRO as a new conceptual framework to understand sepsis” Pediatr Crit Care Med 2005; 6(3 Suppl):S55-60; Poeze et al., “An international sepsis survey: a study of doctors' knowledge and perception about sepsis” Crit Care Med. 2004; 8(6):R409-413; and Ferrer et al., “Improvement in process of care and outcome after a multicenter severe sepsis educational program in Spain” JAMA 2008; 299(19):2294-2303. As more patients than ever have sepsis, even small improvements in recognition and tailored treatment may save many lives. Lagu et al., “Hospitalizations, costs, and outcomes of severe sepsis in the United States 2003 to 2007” Critical Care Medicine 2012; 40(3):754-761; Rivers et al., “Early goal-directed therapy in the treatment of severe sepsis and septic shock” N Engl J Med 2001; 345(19):1368-1377; and Jones et al., “Lactate clearance vs central venous oxygen saturation as goals of early sepsis therapy: a randomized clinical trial” JAMA 2010 303(8):739-746.
To this end, hundreds, if not thousands, of diagnostic and prognostic biomarkers are proposed in sepsis. Pierrakos et al., “Sepsis biomarkers: a review” Critical Care Med. 2010; 14(1):R15. These include markers from a variety of biofluids and organs that capture activation of the innate immune response, coagulation cascade, and impaired organ perfusion. Calvano et al., “A network-based analysis of systemic inflammation in humans” Nature 2005; 437(7061):1032-1037; and Cohen J., “The immunopathogenesis of sepsis” Nature 2002; 420(6917):885-891. And yet, few markers successfully guide sepsis treatments, with many notable failures.
To better link new therapies with sepsis mechanisms, the focus of biomarker discovery is increasingly directed towards molecular expression profiles, including gene and protein expression. Wong et al., “Validation of a gene expression-based subclassification strategy for pediatric septic shock” Critical Care Medicine 2011; 39(11):2511-2517; Wong et al., “Genomic expression profiling across the pediatric systemic inflammatory response syndrome, sepsis, and septic shock spectrum” Critical Care Medicine 2009; 37(5):1558-1566; and Xiao et al., “A genomic storm in critically injured humans” J Exp Med 2011; 208(13):2581-2590. Furthest downstream in the biologic system, however, are small metabolites—such as amino acids, carbohydrates, or lipids. These metabolites may offer a more relevant, amplified signature in sepsis and can be measured using techniques such as 1H nuclear magnetic resonance (NMR) spectroscopy or mass spectrometry (MS). Serkova et al., “The Emerging Field of Quantitative Blood Metabolomics for Biomarker Discovery in Critical Illnesses” American Journal Of Respiratory And Critical Care Medicine (2011).
To date, the application of metabolomic (or metabonomic) profiling in sepsis is limited to reports on: i) animal studies (Izquierdo-Garcia et al., “A metabolomic approach for diagnosis of experimental sepsis” Intensive Care Medicine (2011); Liu et al., “Metabolomic analysis of thermally injured and/or septic rats” Burns 2010; 36(7):992-998; Hinkelbein et al., “Alterations in cerebral metabolomics and proteomic expression during sepsis” Curr Neurovasc Res 2007; 4(4):280-288; Xu et al., “A metabonomic approach to early prognostic evaluation of experimental sepsis” J Infect 2008; 56(6):474-481; ii) specific metabolic pathways, such as: a) tryptophan/kynurenine (Changsirivathanathamrong et al., “Tryptophan metabolism to kynurenine is a potential novel contributor to hypotension in human sepsis” Critical Care Medicine 2011 39(12):2678-2683; Darcy et al., “An observational cohort study of the kynurenine to tryptophan ratio in sepsis: association with impaired immune and microvascular function” PLoS One 2011 6(6):e21185; Zeden et al., “Excessive tryptophan catabolism along the kynurenine pathway precedes ongoing sepsis in critically ill patients” Anaesthesia And Intensive Care 2010 38(2):307-316; and Adams-Wilson et al., “The association of the kynurenine pathway of tryptophan metabolism with acute brain dysfunction during critical illness”Critical Care Medicine 2012 40(3):835-841); b) arachidonic acid (Bruegel et al., “Sepsis-associated changes of the arachidonic acid metabolism and their diagnostic potential in septic patients” Critical Care Medicine 2012 40(5):1478-1486); c) arginine metabolism (Gough et al., “The ratio of arginine to dimethylarginines is reduced and predicts outcomes in patients with severe sepsis” Critical Care Medicine 2011 39(6):1351-1358); and d) others (Semmler et al., “Methionine metabolism in an animal model of sepsis” Clinical Chemistry And Laboratory Medicine: CCLM/FESCC 2008 46(10):1398-1402; and Moviat et al., “Contribution of various metabolites to the “unmeasured” anions in critically ill patients with metabolic acidosis” Critical Care Medicine 2008 36(3):752-758.
Other preliminary work focuses on 1H-NMR metabolomic differences in human, sepsis-associated acute lung injury—where glutathione, adenosine, sphingomyelin, and phosphatidylserine differentiated mechanically ventilated cases from healthy controls. Stringer et al., “Metabolic consequences of sepsis-induced acute lung injury revealed by plasma (1)H-nuclear magnetic resonance quantitative metabolomics and computational analysis” American Journal Of Physiology Lung Cellular And Molecular Physiology 2011; 300(1):L4-L11. Yet, it is less clear how the global metabolomic profile is altered in human plasma from subjects with community acquired pneumonia (CAP) or sepsis, nor its potential for mechanism-informed biomarker discovery.